Despite the increased understanding of the complex pathophysiology of sepsis, severe sepsis and septic shock still have very high significant morbidity and mortality. As such, there is an urgent unmet medical need for an effective novel therapy for sepsis patients. A balanced immune response is an essential element of a successful host defense after infection. However, excessive production of pro-inflammatory mediators or cytokines may cause further tissue injury. The autonomic nervous system reflexively regulates inflammatory responses in real time. In the previous grant cycle, we showed that down-regulation of ghrelin, a gut-brain hormone, is partially responsible for sepsis-induced hepatic injury. Ghrelin's beneficial effects are mediated by the sympathetic and parasympathetic nervous systems to regulate the inflammation reaction in sepsis. Recently, we discovered that cold-inducible RNA-binding protein (CIRP) is upregulated in an animal model of sepsis and patients with sepsis, while ghrelin attenuates CIRP levels in animals that underwent sepsis. Administration of recombinant murine CIRP (rmCIRP) in healthy animals induces acute inflammation and causes tissue injury. In addition, anti-rmCIRP antibodies improve survival in sepsis animals. We have determined that TLR4 serves as the CIRP receptor. By using GFP-CIRP expression plasmid, we demonstrated CIRP translocation from the nucleus to cytoplasm after endotoxin stimulation. Furthermore, norepinephrine directly upregulates CIRP expression, while nicotine decreases endotoxin-induced CIRP expression in isolated macrophages. Thus, we hypothesize that the protective effect of ghrelin on sepsis-induced organ injury is at least in part mediated through the autonomic nervous system by controlling the production and release of a novel proinflammatory mediator, CIRP. Accordingly, four specific aims are proposed: (1) to further determine the detrimental effect of CIRP release in sepsis; (2) to further confirm that the beneficial effect of ghrelin in sepsis is mediated through down- regulation of CIRP; (3) to define the mechanism by which neurotransmitters regulate CIRP release at the cellular level; and (4) to develop anti-CIRP therapeutic agents for treating sepsis. The proposed studies should open up a new research arena for the development of innovative therapeutics for patients with sepsis and septic shock.